McGill scientists publish detailed picture of how nutrients and other molecules get into cells

Montreal, March 9, 2004. Scientists at the Montreal Neurological Institute and the Montreal Proteomics Network at McGill University have published the most complete picture to date of the components of the molecular machinery that controls the entry of nutrients and other molecules into cells. In a study published in the Proceedings of the National Academy of Sciences of the USA (PNAS), Dr. Peter McPherson and colleagues used proteomics, the large-scale study of proteins, to identify the protein complement of clathrin-coated vesicles. These vesicles are the vehicles by which cells are able to take up nutrients, such as cholesterol, from their environment. Defects in this uptake process have profound repercussions on cellular function and human health. For example, genetic diseases that lead to deficiencies in cholesterol uptake cause elevations in plasma cholesterol levels and early-onset coronary atherosclerosis. In the brain, problems in the uptake process involving clathrin-coated vesicles can disrupt the transmission of signals between nerve cells. This can lead to a number of disorders including defects in the ability to form new memories.

"Proteins are the workhorses in our cells," explained Dr. McPherson, Associate Professor of Neurology and Neurosurgery, and Anatomy and Cell Biology at the Montreal Neurological Institute (MNI) at McGill University. "Increasingly, we are learning that proteins don't work in isolation, but function in large arrays that form protein machines. Proteomics is exciting because it allows us to breakdown this complex machine into its component parts. We can then figure out how it is assembled, how the proteins interact with one another, and what goes wrong in disease.

"The study from Dr. McPherson and his colleagues is fundamental to our understanding of the cellular uptake process because it provides a comprehensive molecular inventory of the clathrin-coated vesicle. Its results have broad implications for a variety of fields in biology and medicine," said Dr. Pietro De Camilli, Professor of Cell Biology, Yale University School of Medicine and Investigator, Howard Hughes Medical Institute.

Dr. McPherson together with postdoctoral fellow, Dr. François Blondeau and other colleagues identified 209 proteins. "About half of the proteins we identified are already known to be associated with clathrin-coated vesicles, validating our approach," said Dr. Blondeau. "The rest are novel proteins or proteins with known function that were not previously known to be involved in this process. This identification allows us to hypothesize on how these proteins function in this essential activity of the cells."

"Dr. McPherson's work is a great example of the unique "Cell Map" approach that the Montreal Proteomics Network has taken to perform proteomics experimentation", said Dr. John Bergeron, Director of the Montreal Proteomics Network. "This work allows us to build a map of the location and function of the proteins in the cell, creating a picture of interacting complexes and networks. Ultimately this map will provide a guide to understanding a large number of human diseases."

In June 2000 researchers announced the first draft version of the human genome sequence. This was important because it spelled out all of the genes that define humans and gave the instructions for making the proteins. Proteins do the functional work in the cell and are much more complex than DNA. The roughly 30,000 human genes lead to more than three hundred thousand different proteins. The ability to rapidly and globally detect proteins represents the next step in biology. Revolutions in technology of mass spectrometry which were honoured by the 2002 Nobel Prize for chemistry, have paved the way for proteomics.

The paper can be viewed online at http://www.pnas.org/cgi/reprint/0308186101v1.pdf.
PNAS is one of the world's most-cited multidisciplinary scientific serials.
PNAS Online receives nearly 4 million hits per month.

This research was supported by the Canadian Institutes of Health Research (CIHR), Valorisation Recherche Quebec, Genome Quebec (Montreal Proteomics Network) and Genome Canada and the Canada Foundation for Innovation.

Dr. Peter McPherson is an Investigator of the Canadian Institutes of Health Research, a Killam Scholar and he holds a William Dawson Chair from McGill. Dr. McPherson received both B.Sc. and M.Sc. degrees from the University of Manitoba and a Ph.D. in Neuroscience from the University of Iowa. He completed his post-doctoral training at Yale University School of Medicine. Dr. McPherson has made fundamental discoveries related to neuronal function and is a leading authority on membrane trafficking. Dr. McPherson joined the faculty at the MNI in 1995 as a fellow of the Alfred P. Sloan Foundation. He has authored more than 65 scientific publications.

Dr. John Bergeron is currently the Robert Reford Professor of Anatomy and Cell Biology, Chairman of the Department of Anatomy and Cell Biology and Director of the Montreal Proteomics Network at McGill University. He earned a B.Sc. from McGill University and a D. Phil. in Biochemistry from Oxford University as a Rhodes Scholar. Dr. Bergeron is a Fellow of the Royal Society of Canada and President elect of the Human Proteome Organisation. Dr. Bergeron is a world expert in proteomics and cell biology and has authored more than 150 scientific articles.

Dr. François Blondeau is a postdoctoral fellow with Dr. Peter McPherson at the Montreal Neurological Institute. Dr. Blondeau received his B.S. in Cellular Biology (option Genetics) from the University of Toulouse (1994). He received both his M.S. Molecular and Cellular Biology (option Developmental Biology) (1996) and his Ph.D. Molecular Biology (2000) from the University of Strasbourg. During his doctoral research he discovered the substrate of a novel family of phosphatases that have been implicated in several neuromuscular disorders (X-linked myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome).

The Réseau Protéomique de Montréal - Montreal Proteomics Network (RPMPN) (www.rpmpn.mcgill.ca) is a network of over 100 researchers in Quebec whose goal is to identify, localize and characterize every protein in every organelle of the mammalian cell. This includes understanding how these proteins interact with each other, and how these interactions vary over time within the dynamic cellular environment.

The CIHR (http://www.cihr-irsc.gc.ca/) is Canada's premier agency for health research. Its objective is to excel, according to internationally accepted standards of scientific excellence, in the creation of new knowledge and its translation into improved health for Canadians, more effective health services and products and a strengthened health care system. CIHR's Institute of Neurosciences, Mental Health and Addiction supports research to enhance mental health, neurological health, vision, hearing, and cognitive functioning and to reduce the burden of related disorders through prevention strategies, screening, diagnosis, treatment, support systems, and palliation.

The Montreal Neurological Institute (www.mni.mcgill.ca) is a McGill University (http://www.mcgill.ca) research and teaching institute, dedicated to the study of the nervous system and neurological diseases. Founded in 1934 by the renowned Dr. Wilder Penfield, the MNI is one of the world's largest institutes of its kind. MNI researchers are world leaders in cellular and molecular neuroscience, brain imaging, cognitive neuroscience and the study and treatment of epilepsy, multiple sclerosis and neuromuscular disorders.

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